CN115501343B - Application of ADU-S100 in preparation of medicine for treating general anesthesia hypothermia - Google Patents
Application of ADU-S100 in preparation of medicine for treating general anesthesia hypothermia Download PDFInfo
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- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
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- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
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Abstract
The invention discloses an application of ADU-S100 in preparing a medicine for treating general anesthesia hypothermia. The research of the invention discovers a new pharmacological action of ADU-S100, namely prevention and treatment of body temperature reduction after general anesthesia; the mechanism is probably that Ucp reduction caused by general anesthetics can be reversed by up-regulating fever-related protein Ucp1, and general anesthesia hypothermia can be improved by increasing STING expression and reducing systemic inflammatory response. ADU-S100 was suggested as a novel therapeutic approach for the prevention and treatment of hypothermia following general anesthesia.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to an application of ADU-S100 in preparing a medicine for treating general anesthesia hypothermia.
Background
Peri-operative low temperature is defined as the decrease of the peri-operative body temperature to <36.0 ℃. The incidence rate of low temperature in the perioperative period is 78.6 percent. The incidence of hypothermia within 2 hours was 56.6%, and after 2 hours the incidence of hypothermia was 100%. American Society of Anesthesiologists (ASA) high score, grade 3-4 surgery, endoscopic surgery, anesthesia time >2 hours, intravenous and irrigant fluids without warming, infusion or rinsing >1000 milliliters significantly increased the incidence of hypothermia. Mild hypothermia may be beneficial because it reduces metabolic rate, reduces oxygen consumption, and increases tissue tolerance to ischemia and hypoxia. But prolonged or severe hypothermia conditions during surgery should be avoided, as it may cause cold fibrillation in the patient, with involuntary repeated skeletal muscle contractions. Cold fibrillation increases oxygen consumption of the organism, causes carbon dioxide to increase, causes acidosis and leads to accelerated metabolism. Thus, hypothermia may cause complications in the circulatory and respiratory systems. Notably, a 1℃decrease in core temperature (i.e., a 2.7% decrease from normal) can lead to a variety of adverse effects including increased transfusion demand, clotting disorders, myocardial hypoxia and arrhythmia, prolonged recovery time, immunosuppression, increased susceptibility to surgical site infection, and altered pharmacokinetics. Hypothermia can also affect patient health, and discomfort caused by chills when recovering from anesthesia is comparable to postoperative pain. The consequences of hypothermia in animals are less well established due to the smaller number of studies reported. Cardiovascular side effects include decreased heart rate and cardiac output and prolonged QT interval. Body temperature is tightly regulated by hormones and cellular metabolism to maintain body temperature stable. However, perioperative hypothermia is common secondary to anesthesia and surgical exposure. The prevention and maintenance of body temperature should begin 1-2 hours prior to anesthesia induction, for which both active and passive warming systems are effective in preventing perioperative low temperature related complications. Thus, there is a need for active body temperature management before, during and after surgery to reduce the risk of perioperative hypothermia.
Disclosure of Invention
The invention provides application of STING agonist in preparing a medicament for treating general anesthesia hypothermia.
Further, the general anesthesia includes general anesthesia after inhalation of an anesthetic, general anesthesia after injection of an anesthetic.
Further, the anesthetic agent includes sevoflurane and esketamine.
Further, STING agonists include agents that promote STING expression, agents that promote STING protein activity.
Further, the reagent for promoting STING gene expression includes a reagent for promoting STING gene expression and a reagent for promoting STING gene expression product.
Further, the reagent for promoting the expression of STING gene includes a reagent for promoting the expression of STING gene mRNA and a reagent for promoting the expression of STING protein.
Further, the agents for promoting the expression of STING genes include agents for promoting the transcription of genes, agents for promoting the translation of genes, agents for promoting the content of STING proteins; the reagent for promoting the STING gene expression product comprises a reagent for promoting the stability of the STING gene expression product, a reagent for promoting the activity of the STING gene expression product and a reagent for promoting the function of the STING gene expression product.
Specifically, the agent for promoting STING gene expression comprises: agents containing STING genes, agents formed by vectors or host cells carrying STING genes, agents containing STING proteins.
Further, agents that promote STING expression include STING overexpression vectors.
As a specific example, the over-expression vector of the present invention is a gene therapy vector in the form of a nucleic acid sequence encoding a STING protein administered to a subject to be treated, i.e., a nucleic acid construct comprising a coding sequence (including translation and stop codons) next to other sequences required for expression of an exogenous nucleic acid, such as a promoter, a Kozak sequence, a polyadenylation (polyA) signal, and the like. Gene therapy vectors for expressing exogenous nucleic acid sequences in a subject are well known in the art. For example, the gene therapy vector may be part of a mammalian expression system. Useful mammalian expression systems and expression constructs have been described in the art. In addition, several mammalian expression systems are commercially available from different manufacturers and can be used in the present invention, such as plasmid or viral vector-based systems, e.g., LENTI-SmartTM (InvivoGen), genScript expression vector, pAdVAntageTM (Promega), viraPowerTM lentivirus, adenovirus expression system (Invitrogen), and adeno-associated virus expression system (CellBiolabs).
For example, the gene therapy vector of the invention may be a viral or non-viral expression vector suitable for introducing an exogenous nucleic acid into a cell for subsequent expression of the protein encoded by the nucleic acid.
The expression vector may be: episomal vectors, i.e., vectors that autonomously replicate in the host cell; or an integrative vector, i.e., a vector that is stably incorporated into the genome of the cell. Expression in a host cell may be constitutive or regulated (e.g., inducible).
The gene therapy vectors of the invention typically include a promoter functionally linked to a nucleic acid encoding a STING protein. The promoter sequence must be compact and ensure strong expression. Preferably, the promoter expresses STING protein in a patient treated with the gene therapy vector.
As an alternative ingredient, the gene therapy vector may include enhancer elements that increase the expression level of STING protein. Examples include the SV40 early gene enhancer and the enhancer of the Long Terminal Repeat (LTR) of Rous sarcoma virus (Rous Sarcabirus) (Gormanet. (1982) Proc. Natl. Acad. Sci. 79:6777). The vector also optionally includes transcription termination sequences and polyadenylation sequences for improving expression of human and/or non-human antigens. For example, suitable transcription terminators and polyadenylation signals may be derived from
SV40(Sambrooketal(1989),MolecularCloning:ALaboratoryManual)。
Any other element known in the art to support expression efficiency or specificity may be added to the expression vector, such as woodchuck hepatitis post-transcriptional regulatory element (wPRE).
To further increase gene expression levels, chimeric introns may be introduced into the gene therapy vectors of the present invention. As used herein, "chimeric intron" refers to an intron that includes portions of at least two different introns derived from two different genes.
The gene therapy vector may be constructed and cloned by standard methods known in the art, such as DNA recombination techniques or chemical synthesis. Standard cloning methods are described in Sambrook et al, 1989, molecular cloning, laboratory Manual, cold spring harbor laboratory Press.
In a particularly preferred aspect, the gene therapy vector is a viral expression vector. The viral vectors used in the present invention typically include a viral genome in which a portion of the native sequence is deleted to introduce a heterologous polynucleotide without disrupting viral infectivity. Viral vectors are well suited for efficient transfer of genes into target cells due to specific interactions between viral components and host cell receptors. Suitable viral vectors that facilitate gene transfer into mammalian cells are well known in the art and may be derived from different types of viruses, e.g., from retroviruses, adenoviruses, adeno-associated viruses (AAV), orthomyxoviruses, paramyxoviruses, papovaviruses, picornaviruses, lentiviruses, herpes simplex viruses, vaccinia viruses, poxviruses, or alphaviruses. For a summary of the different viral vector systems, see Nienhuistal, hematology, vol.16: virusesand BoneMarrow, N.S.Young (ed.), 353-414 (1993).
According to the invention, the gene therapy vector is an adenovirus vector.
Recombinant viral vectors can be produced according to standard techniques. For example, recombinant adenovirus or adeno-associated virus vector can be transmitted in human 293 cells (which provide trans E1A and E1B characteristics) to achieve a ratio of 10 7 ～10 13 Titers in the individual viral particles/mL range. Prior to in vivo application, the viral vectors may be desalted by gel filtration methods (such as agarose columns) and purified by subsequent filtration. Purification reduces potential deleterious effects in the body of the drug delivery vehicle. The administered virus is substantially free of wild-type virus and replication-competent virus. The purity of the virus can be demonstrated by suitable methods, such as sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), followed by silver staining. This applies to both AAV vectors and adenovirus vectors.
As described in the examples below, transduction of the gene therapy vector of the invention into a subject to be treated can be achieved by systemic application, e.g., intravenous, intra-arterial or intraperitoneal delivery of the vector, similar to what has been shown in animal models (katzetal 2012, genethera 19:659-669).
In addition to viral vectors, non-viral expression constructs may also be used to introduce genes encoding proteins or functional variants or fragments thereof into cells or human subjects. Non-viral expression vectors that allow in vivo expression of proteins in target cells include, for example, vectors such as plasmids pBK-CMV, pcDNA3.1, and pZeoSV (Invitrogen, stratagene). Suitable methods for transferring the non-viral vector into the target cell are, for example, liposome transfection, phospho-calcium co-precipitation, DEAE-dextran, and direct DNA introduction using a micro glass tube or the like.
Further, host cells include prokaryotic cells and eukaryotic cells. Examples of commonly used prokaryotic host cells include E.coli, bacillus subtilis, and the like. Common eukaryotic host cells include yeast cells, insect cells, and mammalian cells. Preferably, the host cell is a eukaryotic cell, such as a CHO cell, COS cell, or the like.
In a specific embodiment of the invention, the STING agonist is ADU-S100.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising an anesthetic and a STING agonist.
Further, the anesthetic agent includes sevoflurane and esketamine.
Further, the STING agonist is ADU-S100.
The medicaments of the present invention may be used by formulating pharmaceutical compositions in any manner known in the art. Such compositions comprise the active ingredient in combination with one or more pharmaceutically acceptable carriers, diluents, fillers, binders and other excipients, depending on the mode of administration and the designed dosage form. Therapeutically inert inorganic or organic carriers known to those skilled in the art include, but are not limited to, lactose, corn starch or derivatives thereof, talc, vegetable oils, waxes, fats, polyols such as polyethylene glycol, water, sucrose, ethanol, glycerol and the like, various preservatives, lubricants, dispersants, flavoring agents. Moisturizing means, antioxidants, sweeteners, colorants, stabilizers, salts, buffers and the like may also be added as needed to aid stability of the formulation or to aid in enhancing activity or its bioavailability or to impart acceptable mouthfeel or odor in the case of oral administration, the formulations which may be used in such compositions may be in the form of their original compounds themselves or optionally in the form of their pharmaceutically acceptable salts, the medicaments of the present invention may be administered alone or in various combinations, as well as in combination with other therapeutic agents. The composition so formulated may be administered by any suitable means known to those skilled in the art, as desired. When using pharmaceutical compositions, safe and effective amounts of the agents of the present invention are administered to humans, and the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The medicine of the invention can be prepared into various dosage forms according to the needs. Including but not limited to, tablets, solutions, granules, patches, ointments, capsules, aerosols or suppositories for transdermal, mucosal, nasal, buccal, sublingual or oral use.
The route of administration of the drug of the present invention is not limited as long as it can exert a desired therapeutic effect or prophylactic effect, including but not limited to intravenous, intraperitoneal, intraocular, intraarterial, intrapulmonary, oral, intrathecal, intramuscular, intratracheal, subcutaneous, transdermal, pleural, topical, inhalation, transmucosal, dermal, gastrointestinal, intra-articular, intraventricular, rectal, vaginal, intracranial, intraurethral, intrahepatic, intratumoral. In some cases, the administration may be systemic. In some cases locally.
The dosage of the drug of the present invention is not limited as long as a desired therapeutic effect or prophylactic effect is obtained. The dosage of the therapeutic agent or the prophylactic agent of the present invention can be determined using, for example, the therapeutic effect or the prophylactic effect on a disease as an index.
Other therapeutic agents that may be administered with the agents of the present invention include therapeutic agents that treat and/or prevent general anesthesia hypothermia.
The invention also provides a method of treating general anesthesia hypothermia, the method comprising the steps of: administering to a subject in need thereof a STING agonist as described herein before.
The term "in need of the present invention includes mammals, including but not limited to humans, cows, horses, cats, dogs, rodents or primates. In some embodiments, the individual is a human.
The term "treatment" generally relates to the treatment and physical therapy of a human or animal (e.g., in veterinary applications), wherein some desired therapeutic effect is achieved, such as inhibiting disease progression, and includes reducing the rate of progression, stopping the rate of progression, alleviating symptoms of the disease, ameliorating the disease, and curing the disease. Also included are treatments as a prophylactic means (i.e., prophylaxis). For example, the term "treatment" also includes the use of a patient who has not yet developed a disease but is at risk of developing a disease.
As used herein, "treatment" (and grammatical variations thereof) refers to clinical intervention in an attempt to alter the natural course of the individual being treated, either for prophylaxis or in the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the occurrence or recurrence of a disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of a disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating a disease state, and eliminating or improving prognosis.
Drawings
FIG. 1 shows a graph of the results of ADU-S100 on the effects of sevoflurane inhalation general anesthesia on rectal hypothermia;
in the figure: sevo+ns: sevoflurane + saline group; sevo+a: sevoflurane+adu-S100 group; p <0.05, n=10, two-way ANOVA compared to sevo+ns group;
FIG. 2 shows a graph of the effect of ADU-S100 on the hypothermia caused by general intravenous anesthesia of esketamine, wherein: eske+NS: esketamine + physiological saline group; eske+A: esketamine + ADU-S100 group; p <0.05, n=10, two-way ANOVA compared to eske+ns group;
FIG. 3 shows a Western blot experimental result diagram of Ucp 1; wherein A: immunoblot image; b: statistical plot, in which: sevo+ns: sevoflurane + saline group; sevo+a: sevoflurane+adu-S100 group; eske+NS: esketamine + physiological saline group; eske+A: esketamine + ADU-S100 group; n=4; set P <0.01 compared to set sevo+ns; group Eske+A, compared to group Eske+NS, $P <0.01; one-way ANOVA;
FIG. 4 shows a Western blot experiment result diagram of STING; wherein A: immunoblot image; b: statistical plot, in which: sevo+ns: sevoflurane + saline group; sevo+a: sevoflurane+adu-S100 group; eske+NS: esketamine + physiological saline group; eske+A: esketamine + ADU-S100 group; n=4; set P <0.01 compared to set sevo+ns; group Eske+A, compared to group Eske+NS, $P <0.01; one-way ANOVA.
Detailed Description
The invention will now be described in further detail with reference to the drawings and examples. The following examples are only illustrative of the present invention and are not intended to limit the scope of the invention. The experimental procedure, without specific conditions noted in the examples, is generally followed by conventional conditions, such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring HarborLaboratory Press, 1989) or as recommended by the manufacturer.
Examples
1. Experimental procedure
1. Experimental grouping
Male SD mice were purchased from the experimental animal center of the military medical science sciences of the civil liberation army of china 24, 1 month old. The random number table method was used to divide into 4 groups (n=6):
sevoflurane+saline group (sevo+ns group): heptafluoroether is anesthetized for 2.5% anesthesia, followed by continuous infusion of physiological saline 0.2 ml.kg through the abdominal cavity -1 ·h -1 For 60min;
sevoflurane+adu-S100 group (sevo+a group): sevoflurane for 2.5% anesthesia followed by continuous intraperitoneal infusion of ADU-S10020 mg.kg -1 ·h -1 For 60min;
esketamine + physiologySaline group (eske+ns group): abdominal injection of esketamine 100mg/kg followed by continuous intraperitoneal infusion of physiological saline 0.2 ml/kg -1 ·h -1 For 60min;
esketamine + ADU-S100 group (Eske + a group): abdominal injection of esketamine 100mg/kg followed by continuous intraperitoneal infusion of ADU-S10020 mg.kg -1 ·h -1 The total time is 60min.
2. Rectal body temperature monitoring
Rectal body temperature monitoring was started immediately after anesthesia: the rectal body temperature was measured 5min (-5 min) before anesthesia, immediately after disappearance of the non-eversion reflex (0 min), 5, 10, 15, 20, 60min after the start of infusion, and was the core temperature. Laboratory temperature 22 ℃.
3、Westernblot
Each mouse was sacrificed after the last 1 body temperature test, the hypothalamus was taken and hypothalamus Ucp, STING and GAPDH protein expression was determined by Western blot. Hypothalamus was added with pre-chilled tissue protein lysate and ground to tissue homogenate. Centrifuging the homogenate at 4 ℃ for 5min at 12000rpm with a radius of 10cm, and obtaining the supernatant as the total protein of hypothalamic tissues. The extracted protein was denatured at 95℃for 5min. Separating by 10% SDS-PAGE, transferring protein to PVDF membrane with loading amount of 15 μl, adding 5% skimmed milk powder, sealing at room temperature for 2 hr, washing, adding primary antibody, anti-rabbit Ucp, STING antibody and anti-rabbit GAPDH antibody (1:1000, abcam company, USA), incubating at 4deg.C overnight, washing with TBST for 3 times, each time for 5min, adding goat anti-rabbit secondary antibody or goat anti-mouse secondary antibody (dilution 1:2000, ab-Narcissus-Hemsleyae biological Co., ltd., beijing) for 2 hr, washing with TBST for 3 times, each time for 5min, adding luminescent agent in darkroom, exposing, scanning, and imaging. Analyzing the band gray value by using Gene Tools image analysis software, and reflecting the target protein expression level by using the ratio of Ucp1, STING protein band gray value and GAPDH band gray value
4. Statistical analysis
The SPSS 23.0 statistical software is adopted for analysis, the normal distribution measurement data is expressed by mean ± standard deviation (±s), the measurement data of the random block design is compared by single factor analysis of variance, the measurement data of the repeated measurement design is compared by repeated measurement design analysis of variance, and P <0.05 is the difference and has statistical significance.
2. Experimental results
(1) General anesthesia can cause perioperative hypothermia
Compared with 5min before anesthesia, the intake of sevoflurane into general anesthesia or the intravenous general anesthesia of esketamine can cause the body temperature reduction after the post-infusion to be basically stable from 5min after general anesthesia to 20min, and the body temperature is not statistically different from 20min after general anesthesia at 60min after general anesthesia. Indicating that the body temperature drops most rapidly and reaches a lower level 20min after general anesthesia. (all P < 0.05) (fig. 1).
(2) ADU-S100 infusion can reduce hypothermia after general anesthesia
As shown in FIG. 1, the temperature was raised by 0.27℃compared with the pure sevoflurane anesthesia (Sevo+NS) 5min after the infusion of sevoflurane general anesthesia combined with ADU-S100 (Sevo+A); the temperature is increased by 0.42 ℃ compared with the temperature of pure sevoflurane anesthesia (sevo+NS) 10min after the injection of sevoflurane general anesthesia combined with ADU-S100 (sevo+A); the temperature is increased by 0.35 ℃ compared with the temperature of pure sevoflurane anesthesia (sevo+NS) 15min after the injection of sevoflurane general anesthesia combined with ADU-S100 (sevo+A); the temperature is increased by 0.3 ℃ compared with the temperature of pure sevoflurane anesthesia (sevo+NS) 20min after the injection of sevoflurane general anesthesia combined with ADU-S100 (sevo+A); the temperature of the patient is increased by 0.25 ℃ compared with that of pure sevoflurane anesthesia (sevo+NS) 60min after the injection of sevoflurane general anesthesia combined with ADU-S100 (sevo+A).
The results are shown in FIG. 2, and the body temperature is increased by 0.25 ℃ compared with the simple esketamine anesthesia (Eske+NS) 5min after the esketamine general anesthesia and ADU-S100 infusion (Eske+A); the body temperature of the esketamine after 10 minutes of infusion (Eske+A) of the general anesthesia combined with ADU-S100 is increased by 0.35 ℃ compared with that of the pure esketamine anesthesia (Eske+NS); 15min after the general anesthesia of the esketamine and the ADU-S100 are infused (Eske+A), the body temperature is increased by 0.36 ℃ compared with the simple anesthesia of the esketamine (Eske+NS); the body temperature of the esketamine 20min after the general anesthesia combined with ADU-S100 infusion (Eske+A) is increased by 0.42 ℃ compared with the body temperature of the esketamine only after anesthesia (Eske+NS); the body temperature is increased by 0.35 ℃ compared with the pure esketamine anesthesia (Eske+NS) 60min after the esketamine general anesthesia and ADU-S100 infusion (Eske+A).
Rectal temperature monitoring proves the positive effect of ADU-S100 on body temperature reduction after general anesthesia, and has obvious body temperature protection effect. Continuous infusion of ADU-S10020 mg.kg into abdominal cavity -1 ·h -1 Can reduce body temperature decrease caused by general anesthesia.
(3) ADU-S100 may alleviate hypothermia caused by general anesthesia by increasing Ucp1 expression
As shown in FIG. 3, ADU-S100 increased the expression of mouse Ucp1, suggesting that ADU-S100 may increase brown fat thermogenesis by increasing Ucp1 expression. In addition, STING was found to be elevated following ADU-S100 infusion, possibly by reducing systemic inflammatory responses, thereby improving systemic hypothermia (fig. 4).
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate that: many modifications and variations of details may be made to adapt to a particular situation and the invention is intended to be within the scope of the invention. The full scope of the invention is given by the appended claims together with any equivalents thereof.
Claims (3)
- Use of adu-S100 in the manufacture of a medicament for the treatment of general anesthesia hypothermia.
- 2. The use according to claim 1, wherein said general anesthesia comprises general anesthesia after inhalation of an anesthetic, general anesthesia after injection of an anesthetic.
- 3. The use according to claim 2, wherein the anesthetic comprises sevoflurane, esketamine.
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